3. Autophagy
• Auto-phagy = Self- eating
• Autophagy is a lysosomal degradation pathway that
is essential for survival, differentiation, development,
and homeostasis.
• Autophagy principally to protect organisms against
diverse pathologies, including infections, cancer,
neurodegeneration, aging, and heart disease.
• First autophagy in rat liver cells
6. Autophagy in immune system
Autophagy is most ancient of immune
defences.
Autophagy has now evolved multifacetted
role.
Autophagy has now become a bonafide
regulator of both innate and acquired
immune system.
7. Autophagy in innate immunity
Autophagy and pattern
recognition patterns.
Autophagy and bacteria
handling.
Autophagy and cytokines.
8. TLR4 is able to induce
autophagy in murine
macrophages following
stimulation with
lipopolysaccharide
(LPS). ( Shi CS, Kehrl JH.)
• LPS stimulation of
TLR4 was shown to
increase the clearance
of Mycobacterium
tuberculosis by
autophagy. (xu Y, Jagannath C,
Liu XD)
• TLR9 Front. Immunol., 25 June 2014
Autophagy and PRRs
9. Autophagy and NLRs
• Activation of the NLRs in mice
leads to recruitment of
Atg16L1 at the plasma
membrane to the site entry of
invading Shigella flexneri and
Listeria monocytogenes,
resulting in their sequestration
in autophagosomes and
subsequent destruction. Travassos
LH, Carneiro LA, Ramjeet M et al.)
Annual Reviews
10. Annual Reviews
In humans, the treatment of
DCs with the NOD2 ligand
muramyldipeptide (MDP) has
been shown to induce autophagy
(Cooney R, Baker J, Brain O et al.)
11. Autophagy and NLRS
• NLRs induce autophagy
• Absence of NOD2 signalling resulted in increased
bacterial burden, attributed to poor autophagy
induction. (Lapaquette P, Bringer M, Darfeuille-Michaud A.)
12. NLRs can also inhibit autophagy
• NLRP4 can inhibit
autophagy through its
ability to bind and inhibit
the action of Beclin 1.
Front. Immunol., 21 November 2013
13. Autophagy and RLRs
• Acts downstream of virus-sensing pathways
mediated by RLRs.
• Treatment with the polyinosine-polycytidylic acid,
acting through the RLR is able to induce autophagy
in melanoma cells resulting in autophagy-dependent
cell death.(Tormo D, Checinska A, Alonso-Curbela D et al)
14. Negative regulation of RLRs by autophagy
• Atg5-deficient murine macrophages have increased
RLR signalling mediated by enhanced reactive
oxygen species production owing to an increase in
mitochondrial volume.(Tal MC, Sasai M, Lee HK, Yordy B, Shadel GS,
Iwasaki A)
15. Autophagy and cytokines
• Interferon- γ ((Th1) cytokine ) is a potent inducer of
autophagy while the IL-4 and IL-13(Th2 cytokines ) have
been shown to have inhibitory effect
• Production of multiple other cytokines is enhanced in the
absence of autophagy
• Increases in IL-1α, IL-12, IL-17 and CXCL1 were all observed
in Atg5 fl/fl LysM-Cre+ mice compared with wild-type controls
in response to M. tuberculosis infection.
16. Autyophagy and cytokines
• Role in the biogenesis and secretion of various proinflammatory
cytokines.
• Atg16L1-deficient macrophages exhibit enhanced IL-1 β and
IL-18 secretion following stimulation with LPS.
• TNF-α and IL-6 secretion are also regulated by autophagy;
• Inhibition of autophagy with 3-MA or knockdown of beclin 1
and Atg7 promotes IL-1α, IL-1β and IL-23 secretion by
macrophages and DCs and this in turn augments innate secretion
of IL-17, IFN-γ and IL-22 by γδ T cells.
18. Autophagy and adaptive immunity
Autophagy and antigen presentation
• MHC Class I presentation
• MHC Class II presentatioin
Autophagy in T cells
Autophagy in B cells
19. Autophagy and antigen presentation
MHC Class I presentation
• Limited evidence exists that autophagy plays a
role in the conventional MHC class I pathway.
• No improvement in MHC class I presentation of a
viral epitope when it was conjugated to LC3, a
mechanism that was able to enhance the
presentation of MHC class II antigens.(Schmid D, Pypaert
M, Munz C)
• Multiple other studies have also failed to report a
requirement for autophagy in MHC class I
presentation.(Lee HK, Mattei LM, Steinberg BE et al.)
20. Autophagy and MHC Class I….
Inhibition of autophagy was found to decrease
MHC class I surface expression in B16 murine
melanoma cells and subsequent tumour cell
cytolysis by CD8+ T cells.(Li B, Lei Z, Lichty BD, et al)
Autophagy has been implicated in an alternative
pathway of MHC class I presentation that exists in
DCs and macrophages, termed cross-presentation.
22. Autophagy and antigen presentation
MHC Class II presentatioin
Prominent role of the lysosomal system in MHC
class II presentation have linked autophagy to this
form of antigen presentation.
Traditionally, MHC class II antigens were believed
to be sourced from the extracellular space following
phagocytosis by antigen-presenting cells.
23. MHC Class II …
• More than 50% of MIICs were observed to receive
input from autophagosomes.(Schmid D, Pypaert M, Munz C)
• Analysis of the human B lymphoblastoid cell line
showed that some MHC class II epitopes were
derived from intracellular sources and starvation-
induced autophagy could enhance the presentation
of intracellular antigens on MHC class II
molecules.(Dengjel J, Schoor O, Fischer R et al.)
24. MHC Class II…
Use of starvation and Rapamycin in macrophages
and DCs can also increase MHC class II
expression of a mycobacterial antigen following
phagocytosis of BCG (Gerland LM)
The secreted antigen, Ag85B, was found colocalized
with LC3+ autophagosomes suggesting that
autophagy may capture antigens following their
escape from the phagosome and deliver them to the
lysosome to prime CD4+ T cells.
25. MHC Class II…
• Conjugation of the influenza matrix protein 1 to
LC3 could also enhance the priming of antigen-
specific CD4+ T cells.
• Mice with a DC-specific deletion of Atg5 have
impaired CD4+ T-cell priming in response to
herpes simplex virus infection (Lee HK, Mattei LM, Steinberg
BE et al)
27. Autophagy and T cells
Autophagy is constitutively present in T cells (Gerland
LM et al)
T cell development and selection (Nedjic J, Aichinger M,
Emmerich)
T cell deletion in Atg5-/- leads to increased apoptosis
due to loss of organelle quality.(Parekh VV, Wu L, Boyd KL et al.)
Proliferation following activation by Ag(Wang X, Gao Y,
Tan J et al.)
Loss of ER homeostasis (Jia W, He Y)
Regulation of energy metabolism (Hubbard VM, Valdor R,
Patel B)
iNKT cell development(Parekh VV, Wu L, Boyd KL et al.)
28.
29. Autophagy and B cells
B cell development (Miller BC, Zhao Z, Stephenson LM et al.)
B cell homeostasis (Mortensen M, Ferguson DJ, Edelmann M, Kessler B,
Morten KJ, Komatsu, Simon AK. et al)
Differentiation of B cells into Plasma cells (Pengo N,
Scolari M, Oliva L et al.)
Regulated Ig secretion
30.
31. Conclusion
Autophagy is implicated in pathogen sensing, phagocytosis, the
removal of intracellular pathogens, and cytokine production.
Role of autophagy in MHC Class II well known but in Class I not
understood
Autophagy is essential for the homeostasis of lymphocytes
Role of autophagy in certain functions of immune system is
unclear and needs further work
32. References
• Autophagy in the immune system :Daniel J. Puleston1 and Anna Katharina Simon
• journal of immunology published by John Wiley & Sons Ltd, Immunology, 141, 1–8 :2013
• Autophagy and cytokines :James Harris Immunology Research Centre, School of
Biochemistry & Immunology, Trinity College Dublin, College Green, Dublin 2, Ireland
• Autophagy and Its Role in MHC-Mediated Antigen Presentation :Victoria L. Crotzer and
Janice S. Blum J Immunol 2009;
• Autophagy and pattern recognition receptors in innate immunity; Monica
Delgado,Sudha Singh,Sergio De Haro ,Sharon Master etal Immunological Reviews 2009 Vol.
227: 189–202
• TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate
immunity :Emma M. Creagh and Luke A.J. O’Neil TRENDS in Immunology Vol.27 No.8
• Autophagy and the Immune System: Petric Kuballa, Whitney M. Nolte, Adam B.
Castoreno, and Ramnik J. Xavier Annu. Rev. Immunol. 2012. 30:611–46
• Pattern recognition receptors and autophagy Ji Eun Oh and Heung Kyu Lee Front.
Immunol., 25 June 2014 | doi: 10.3389/fimmu.2014.00300
